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| Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis |
| Xiao-hua Xu, Yi-chao Gan, Gen-bo Xu, Ting Chen, Hong Zhou, Jin-fen Tang, Ying Gu, Fei Xu, Ying-ying Xie, Xiao-ying Zhao, Rong-zhen Xu |
| Department of Hematology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China; Department of Cancer Institute, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China |
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Abstract Objective: To evaluate the effects of tetrandrine citrate, a novel tetrandrine salt with high water solubility, on the growth of imatinib (IM)-resistant chronic myeloid leukemia (CML) in vitro and in vivo, and reveal action molecular mechanisms. Methods: Cell viability in vitro was measured using methyl thiazolyl tetrazolium (MTT) assay. CML cell growth in vivo was assessed using a xenograft model in nude mice. Bcr-Abl and β-catenin protein levels were determined using Western blotting. Bcr-Abl messenger RNA (mRNA) was measured by reverse transcription polymerase chain reaction (RT-PCR). Flow cytometry (FCM) was used to determine cell cycle status. Results: Tetrandrine citrate inhibited the growth of IM-resistant K562 cells, primary leukemia cells, and primitive CD34+ leukemia cells, and their inhibition concentration that inhibited 50% of target cells (IC50) ranged from 1.20 to 2.97 μg/ml. In contrast, tetrandrine citrate did not affect normal blood cells under the same conditions, and IC50 values were about 10.12–13.11 μg/ml. Oral administration of tetrandrine citrate caused complete regression of IM-resistant K562 xenografts in nude mice without overt toxicity. Western blot results revealed that treatment of IM-resistant K562 cells with tetrandrine citrate resulted in a significant decrease of both p210Bcr-Abl and β-catenin proteins, but IM did not affect the Bcr-Abl protein levels. Proteasome inhibitor, MG132, did not prevent tetrandrine-mediated decrease of the p210Bcr-Abl protein. RT-PCR results showed that tetrandrine treatment caused a decrease of Bcr-Abl mRNA. FCM analysis indicated that tetrandrine induced gap 1 (G1) arrest in CML cells. Conclusions: Tetrandrine citrate is a novel orally active tetrandrine salt with potent anti-tumor activity against IM-resistant K562 cells and CML cells. Tetrandrine citrate-induced growth inhibition of leukemia cells may be involved in the depletion of p210Bcr-Abl mRNA and β-catenin protein.
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Received: 14 January 2012
Published: 05 November 2012
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Cite this article:
Xiao-hua Xu, Yi-chao Gan, Gen-bo Xu, Ting Chen, Hong Zhou, Jin-fen Tang, Ying Gu, Fei Xu, Ying-ying Xie, Xiao-ying Zhao, Rong-zhen Xu. Tetrandrine citrate eliminates imatinib-resistant chronic myeloid leukemia cells in vitro and in vivo by inhibiting Bcr-Abl/β-catenin axis. Journal of Zhejiang University-SCIENCE B (Biomedicine & Biotechnology), 2012, 13(11): 867-874.
URL:
http://www.zjujournals.com/xueshu/zjus-b/10.1631/jzus.B1200021 OR http://www.zjujournals.com/xueshu/zjus-b/Y2012/V13/I11/867
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